Abstract
To analyze how estrogen blocks osteoclastogenesis, we investigated the effects of ovariectomy on osteoclast (OC) formation in co-cultures of purified OC precursors and purified stromal cells (SC). OC formation was higher in co-cultures containing SC from ovariectomized mice than in those containing SC from sham-operated mice, thus suggesting that estrogen regulates osteoclastogenesis by targeting SC. Ovariectomy also increased the mononuclear cell secretion of interleukin (IL)-1) and tumor necrosis factor (TNF) and the SC production of macrophage colony-stimulating factor (MCSF). Osteoclastogenesis and SC production of M-CSF were not blocked by in vitro estrogen treatment but were decreased by in vivo treatment of donor mice with either estrogen or a combination of the IL-1 inhibitor, IL-1 receptor antagonist, and the TNF inhibitor, TNF binding protein. IL-1 and TNF production were also blocked by in vivo estrogen treatment, demonstrating that the increased bone marrow levels of IL-1 and TNF characteristic of ovariectomized mice induce the formation of a SC population characterized by a high production of M-CSF and increased pro-osteoclastogenic activity. Since in co-cultures of SC and OC precursors M-CSF levels correlated with OC production (r = 0.7, p < 0.0001), the data also indicate that the pro-osteoclastogenic activity of SC is proportional to their secretion of M-CSF. The ability of estrogen to decrease SC production of M-CSF and the pro-osteoclastogenic activity of these cells by regulating IL-1 and TNF production is a previously undescribed mechanism by which estrogen down-regulates osteoclastogenesis.
Highlights
It is recognized that one of the main mechanisms by which estrogen blocks bone loss is inhibition of proliferation and differentiation of osteoclast (OC)1 precursors [1]
We report that the increased bone marrow cell production of IL-1 and tumor necrosis factor (TNF) caused by estrogen deficiency leads to the expansion of a stromal cells (SC) population characterized by a high production of M-CSF and increased proosteoclastogenic activity
To investigate whether ovariectomy increases osteoclastogenesis via an effect on OC precursors, nonadherent bone marrow cells obtained from OVX and shamoperated were stimulated with 1,25(OH)2D3 and co-cultured with ST2 stromal cells, a cloned cell line that promotes OC formation from bone marrow cells, spleen cells, and monocytes [29]
Summary
It is recognized that one of the main mechanisms by which estrogen blocks bone loss is inhibition of proliferation and differentiation of osteoclast (OC) precursors [1]. SC contribute to osteoclastogenesis by providing a physical support for nascent OCs and by producing soluble and membrane-associated factors that stimulate the proliferation and/or the differentiation of hematopoietic OC precursors [3]. Among these factors are M-CSF [3,4,5], interleukin (IL)-6 [6], and IL-11 [7]. SC production of M-CSF is induced by IL-1 and tumor necrosis factor (TNF) ␣ and  [8, 9], cytokines produced mainly by bone marrow mononuclear cells [10, 11] and recognized for their ability to promote OC formation and bone resorption [12, 13]. We report that the increased bone marrow cell production of IL-1 and TNF caused by estrogen deficiency leads to the expansion of a SC population characterized by a high production of M-CSF and increased proosteoclastogenic activity
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